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Since December 2019, the COVID-19 pandemic has caused widespread mortality and adverse economic impact throughout the world. Though predominantly a respiratory disease, concerns regarding cardiovascular effects have been highlighted. Cardiac biomarkers and their elevations in COVID-19 have been associated with higher cardiovascular disease burden and worse prognosis. The mechanism of cardiac enzyme elevation in COVID-19 can be explained under two broad categories- direct injury caused by downregulation of ACE2 and hypoxemia, and indirect injury, which is mediated by the cytokine storm. Cardiac troponin and high sensitivity troponin are the most extensively studied cardiac enzymes in COVID-19. Studies have shown comparable and in some cases better predictive value than traditional markers of inflammation like d-dimer, C-reactive protein, lactate dehydrogenase. Natriuretic peptides such as BNP have utility as a robust prognostic marker in COVID-19 when considering outcomes like the need for mechanical ventilation and mortality. Emerging data from studies investigating the role of newer cardiac biomarkers in COVID-19 like mid-regional proadrenomedullin, growth differentiation factor-15 have also yielded promising results. As advances are made in our understanding of the pathogenesis, diagnosis, and management of COVID-19, it is evident that investigating the role of cardiac biomarkers in COVID-19 provides vital information.
Department of Internal Medicine, University of Connecticut, United States
Abhishek Madathanapalli
Department of Internal Medicine, University of Connecticut, United States
Raj Parikh*
Division of Pulmonary and Critical Care Medicine, Hartford Hospital, United States
*Address all correspondence to: raj.parikh210@gmail.com
1. Introduction
In December 2019, unexplained cases of pneumonia were reported from the epicenter of Wuhan City in China caused by a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The transmissibility and virulence of this virus quickly transformed it into the worst global pandemic of our generation. The viral pneumonia syndrome was then named coronavirus disease 2019 (COVID-19) by World Health Organization. The COVID-19 pandemic continues to be a major cause of mortality and economic impact throughout the world. It is predominantly a respiratory disease, with a range of presentations varying from asymptomatic to severe respiratory failure. SARS-CoV-2 is known to enter human cells through angiotensin-converting enzyme 2, which is expressed not only in the lungs but also in other organs, such as the cardiovascular system, thus explaining the wide range of symptom manifestations. Significant concerns relating to COVID-19 and the cardiovascular system have been highlighted, with COVID-19 inducing multiple cytokines and chemokines resulting in vascular inflammation, plaque instability, and myocardial inflammation. Several biomarkers have been studied that have related to COVID-19 progression as well as short-term mortality [1]. Cardiac biomarker and their elevation in COVID-19 have been studied and shown as a reflection of myocardial injury, hemodynamic stress, higher burden of cardiovascular disease, and worse prognosis [2]. Cardiac biomarkers have been suggested as possible aids for clinicians treating COVID-19 and understanding the severity of the disease and prognosis of patients. In this chapter, we will discuss the pathogenesis, role of specific cardiac biomarkers, and their use in the prognosis and management of COVID-19.
The COVID-19 pandemic ranks as one of the most devastating events of the 21st century. Since 2019, the virus has spread rapidly across the globe with a reported case burden of upwards of 219 million with 4.5 million deaths. The United States of America, India, and Brazil reported the highest mortality among countries across the globe. The Centers for Disease Control and Prevention (CDC) estimates put the total number of COVID-19 cases in the United States at 44 million with 709,000 deaths. There is emerging data regarding the incidence and prevalence of cardiac injury in COVID-19 infection. Systematic reviews and meta-analyses have shown wide-ranging results. One meta-analysis demonstrated a 19% prevalence of cardiac injury in total COVID-19 cases, with 36% prevalence in severe cases, and 48% prevalence in non-survivors. Another meta-analysis showed a cardiac injury prevalence of 7.2% in total COVID-19 survivors, and 77% in non-survivors. While further analysis needs to be carried out to establish a more accurate prevalence of cardiac injury in COVID-19 infection, the prevalence of cardiac injury tends to increase along with the severity of the infection and poorer prognosis.
The pathobiology of elevation of cardiac enzymes in patients with COVID-19 can be divided into two major categories: (1) direct damage to the heart by downregulation of ACE2, microvascular dysfunction, pericyte injury, and hypoxemia causing: myocarditis, heart failure, arrhythmias; and (2) indirect damage of cytokine storm by the release of cytokines, hyper inflammation, insulin resistance, coagulopathy causing: myocarditis, metabolic effect, thromboembolism. These are elucidated in Figures 1 and 2. Potential mechanisms of myocardial injury in COVID-19 include binding of the SARS-CoV2 virus to the endothelial angiotensin-converting enzyme 2 (ACE-2) receptor [3]. Given the low overall expression of angiotensin-converting enzyme 2 receptor in myocardial cells, the tropism of severe acute respiratory coronavirus 2 for the heart may be less likely. Myocardial injury has been reported in 36% patients hospitalized with COVID-19. Although clinical COVID-19 cases with myocardial injury and normal coronary arteries have been thought to be caused by myocarditis, ST-segment elevation myocardial infarctions (STEMI) may be caused by extensive microvascular thrombosis in the absence of epicardial coronary obstruction. On the other hand, indirect injury can occur as a consequence of a proinflammatory state, stress cardiomyopathy, and tachyarrhythmia attributable to endogenous or exogenous adrenergic stimulation. Systemic infections such as pneumonia have a profound effect on the cardiovascular system, including an increase in oxygen consumption and coronary plaque vulnerability. Myocardial involvement caused by cytokine storm or cardiomyocyte apoptosis triggered by excessive intracellular calcium in response to tissue hypoxia constitutes the indirect response of COVID-19 [4]. Myocardial ischemia occurs in the setting of shock, prolonged tachycardia, or severe respiratory failure, known as type 2 acute myocardial injury (AMI) or acute atherothrombosis, known as type 1 AMI. Type 1 myocardial infarction occurs in the setting of atherothrombosis, which may be triggered by a proinflammatory and prothrombotic state. Type 2 myocardial infarction is most likely in patients with prolonged oxygen supply or demand imbalance with hypoxia, hypotension, or tachycardia. Finally, both myocarditis and takotsubo syndrome have been reported in patients with confirmed COVID-19 and in those without COVID-19 who had experienced severe anxiety due to the pandemic or with concomitant infections.
Figure 1.
Cardiac phenotypes of manifestations of COVID-19.
Figure 2.
Mechanisms of cardiac Injury of COVID-19 with clinical sequelae.
Cardiac troponin (cTn) is a well-studied and commonly used marker of cardiovascular disease. Troponin is a calcium-regulatory protein for the calcium regulation of contractile function in skeletal and cardiac muscles. Troponin is a complex of three different subunits, troponins C, I, and T, which share characteristic functions of troponin, such as the binding of Ca2+ (troponin C), the inhibition of actomyosin interaction (troponin I), and the binding to tropomyosin (troponin T). Troponin is nearly undetectable in unaffected muscle, but troponin levels rise several hours after the onset of myocardial injury. Elevated levels of troponin have been used as a widely accepted marker of cardiac injury. It is detectable up to 10 days after the onset of injury. The degree of elevation of troponin also gives prognostic information on the subsequent outcome as seen in Figure 3. Cardiac troponin I levels of 1.0 μg/L or higher or cardiac troponin T levels of 0.1 μg/L or higher are considered elevated. Circulating cTn is a marker of myocardial injury, including but not limited to myocardial infarction or myocarditis. There has been growing evidence of higher mortality rates among patients among those patients with underlying cardiovascular disease. The values of cardiac troponin and its elevations above normal concentrations in a patient with COVID-19 should be seen as the combination of the presence or extent of pre-existing cardiac disease and the acute myocardial injury related to COVID-19 and its complications. It further acts as a quantitative marker of this injury. It has been proposed that there are three phases of troponin elevation: first, when cardiac troponin increases mostly reflect ongoing comorbidities, commonly seen at the time of are admission; second, with a critical illness like ARDS; third, specific COVID-19 complications such as pulmonary embolism, stroke, endothelitis and myocarditis. Patients with COVID-19 admitted to the hospital, at 30-day follow up with higher cTn (concentrations greater than ≥21 ng/L) have been associated independently with a higher risk of all-cause mortality. Cardiac troponin elevations, even in small amounts (≥21 ng/L) provide a better prediction of 30-day all-cause mortally and severe course of the disease than other commonly used biomarkers for inflammation including C-reactive protein (CRP), lactate dehydrogenase (LDH), and D-dimer. Furthermore, greater elevations (cTn > 90 ng/L) correlate with higher risk of death than small concentrations (cTn > 30–90 ng/L). Patients with cTn concentrations in the third centile had about six times the all-cause mortality as well as cardiovascular mortality as compared to patients in the first tertile. Higher troponin concentrations are also related to a higher risk of death within 30 days as well as 2 years. Concentrations remained in the normal range in the majority of survivors. High sensitivity troponin I (hs-TnI) is a newer, more sensitive marker of disease progression and mortality in patients with cardiac disease [5]. It was established to be a better marker than those used to determine generalized inflammation including D-dimer and lymphocyte count. Raised hc-TnI in patients admitted with COVID-19 has also been showed to correlate with increased requirements of invasive as well as non-invasive ventilation, development of acute respiratory distress syndrome (ARDS) as well as acute kidney injury (AKI). Studies revealed that the elevated hs-TnI levels were closely correlated with the prognosis and mortality risk of COVID-19 patients. Specifically, the mortality risk increased by 20.8% when the hs-TnI level increased by 1 unit in one such study. However, it is noteworthy to remember that elevated levels are common in hospitalized patients, and are most commonly in the setting of type 2 myocardial infarction (myocardial oxygen supply-demand imbalance) or non-ischemic causes of myocardial injury. Marked elevations of cardiac troponin in patients without critical illnesses such as ARDS, may indicate the presence of takotsubo syndrome, myocarditis, or type 1 AMI triggered by COVID-19. In the absence of symptoms or electrocardiographic changes suggestive of type 1 acute myocardial injury, imaging studies including echocardiography and/cardiac magnetic resonance should be considered to detect left ventricular systolic dysfunction as a new and treatable condition. Patients with symptoms suggestive of type 1 AMI should be treated according to European Society of Cardiology (ESC) guidelines irrespective of COVID-19 diagnosis or suspicion. These patients should undergo rapid coronary angiography under specific catheter personnel. Patients with COVID-19 or other pneumonia who are critically ill with septic shock or ARDS, even marked cardiac troponin elevations are much more likely the consequence of critical illness. The recognition of myocardial injury with elevated cardiac troponin and hs-TnI, given its sensitivity as an early and precise marker of end-organ dysfunction, can prompt timely triage to a critical care unit and informs the measures to improve tissue oxygenation and perfusion with the use of inotropes and vasopressors. Further research is required to elucidate the value of cardiac troponin and high sensitivity troponin I in COVID-19.
Figure 3.
Relationship of troponin T and expected probability of death.
Creatine Kinase (CK) is an intracellular enzyme present primarily in skeletal muscle, myocardium, and brain. Disruption of cell membranes due to hypoxia or other injury releases CK from cytosol to systemic circulation. CK is a dimeric molecule composed of 2 subunits, namely M and B. Combinations of these subunits form the isoenzymes CK-MM, CK-MB, and CK-BB. A significant concentration of CK-MB isoenzyme is found almost exclusively in the myocardium, and therefore elevations in CK-MB levels in serum is highly specific and sensitive for myocardial injury. Normal reference values for CK-MB range from 3 to 5% of total CK, or 5 to 25 IU/L. Creatine Kinase as a marker of myocardial injury has been largely replaced by troponin in clinical practice. As with troponins, several mechanisms explain the elevated cardiac markers in severe COVID-19: viral myocarditis, cytokine-driven myocardial damage, microangiopathy, and unmasked CAD. Myocardial ACE2 receptors are targets for SARS-CoV-2. A hypothesis is that SARS-CoV-2 induces indirect cardiovascular injury through activation of the immune system. The virus attaches to the pattern recognition receptors (PRRs), that initiate host-immune defense. This host-immune defense system, in turn, induces inflammatory reactance that culminates in a cytokine storm. The cytokine storm is caused by the release of reactive oxygen species (ROS), endogenous nitric oxide (NO), and damage-associated molecular proteins (DAMPs) by the injured myocardium that ultimately leads to myocardial injury. Cytokines and host-immune dysregulation cause direct and indirect cardiac injury, leading to an increase in troponin and CK-MB. A meta-analysis showed that when compared with mortality, COVID-19 patients who died had significantly higher biomarkers, including CK-MB. Another meta-analysis showed that there was a significantly higher CK level in patients who died compared to patients who survived, whereas the patients who were critically ill did not have significantly higher CK levels compared to the patients who were not critically ill.
Natriuretic peptides represent a change of intracardial pressure, especially atrial pressure, and thus is also used as an important cardiac function indicator. These include Brain-type natriuretic peptide (BNP), NT-proBNP, and mid-regional pro atrial natriuretic peptide. Nartiuretic peptides are trigger by hemodynamic stress and heart failure, intracardiac filling pressures, end diastolic wall stress, and hypoxemia. In patients who are not critically ill, BNP/pro-BNP elevations have a high positive predictive value for heart failure. However, in patients who are critically ill, the elevations are likely in the presence of hemodynamic stress and heart failure. Several studies have identified heart failure as a significant manifestation of COVID-19. Heart failure in COVID-19 patients is postulated to occur as a result of the severe immune system reaction and cytokine storm [6, 7]. The virus downregulates the angiotensin-converting enzyme 2 (ACE2), leading to increased levels of angiotensin II. Further, this causes increased inflammation, thrombosis, and hypertension. Abnormalities NT-proBNP, were associated with higher in-hospital mortality in all patients and in severe patients. Studies were done to estimate the cumulative in-hospital mortality among patients severe COVID-19 patients. The mortality rates were the highest with elevated hs-cTnI and NT-proBNP, followed by elevated NT-proBNP and normal hs-cTnI, elevated hs-cTnI and normal NT-proBNP, and normal hs-cTnI and NT-proBNP. The combination of these two cardiac markers together was found to be more valuable than cardiac troponin alone in determining the prognosis of COVID-19 patients. There has been one retrospective study that reported a correlation between first and peak BNP values to predict the need for mechanical ventilation and mortality respectively. Pro-BNP levels elevated above 167.5 pg./mL are associated with an increased risk of mortality in patients receiving mechanical ventilation. Furthermore, along with the strong association of mortality in patients admitted to the hospital with COVID-19, the elevation of natriuretic peptides could be used as an early indicator for the presence of left and right ventricular systolic dysfunction independently. Identification of ventricular systolic dysfunction, if a treatable dysregulation, will help in decreased mortality and improved outcomes in patients.
ADM is a multipotent regulatory peptide with several biological activities including vasodilator, positive inotropic, diuretic, natriuretic, and bronchodilator. It is widely expressed throughout the body, including bone, adrenal cortex, kidney, lung, blood vessels, and heart. ADM is even present in pulmonary pneumocytes type 2, smooth muscle cells, neurons, and immune cells. It is upregulated by hypoxia, inflammatory cytokines, bacterial products, and shear stress. As ADM measurement is complicated, mid-regional proadrenomedullin (MR-proADM) is being considered as an estimate of ADM [8, 9, 10]. High levels of MR-proADM are reported in septic patients. These have been shown to be particularly specific in prognostic value, not only for early diagnosis in the context of patients initially presenting to the Emergency Department (ED) but also for risk stratification and prognosis in critically ill patients in Intensive Care Units (ICU). A study from Italy in 2020 aimed to describe the utility of MR-proADM as a prognostic biomarker in severe COVID-19 infection. Fifty seven patients who were admitted to the ICU with COVID-19 infection were studied. Multivariate logistic regression models demonstrated that MR-proADM was an independent predictor of mortality [11].
7.2 GDF-15—growth differentiation factor 15
Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor β superfamily and is widely distributed in low concentrations in most organs [12]. Physiological GDF-15 concentrations increase with age, while the expression is upregulated in pathological states through several pathways that mediate damage to the heart, lungs, liver, and kidneys including inflammation, oxidative stress, and hypoxia. Elevated concentrations of circulating GDF-15 have been identified in multiple disease entities like CVD, sepsis, cancer, and diabetes. GDF-15 levels seem to be a robust predictor of disease progression.
A clinical trial from Norway in 2020 looked at the value of GDF-15 as a biomarker in 123 patients admitted with COVID-19, GDF-15 was elevated in 80% of patients hospitalized with COVID-19, and higher concentrations were associated with SARS-CoV-2 viremia, hypoxemia, and worse clinical outcome. Moreover, GDF15 concentrations were more closely associated with poor outcomes than established biomarkers in COVID-19, including cTnT, NT-proBNP, CRP, and D-dimer. Greater increases in GDF-15 during hospitalization were also independently associated with worse outcomes.
7.3 Cardiac enzymes and prognosis
The prognostic role of cardiac markers in patients hospitalized with COVID-19 is remarkably similar to those in patients with viral pneumonia due to influenza, as well as for pneumonia and ARDS in general in addition to certain unique characteristics. Increased concentrations of cTn, hs-TnI, pro-BNP have been showed to have a correlation with increased mortality and severity of COVID-19 pneumonia [13]. Mild elevations in cardiac troponin concentrations, particularly in older patients with pre-existing cardiac disease, are often explained by the combination of known or unknown pre-existing cardiac disease and acute myocardial injury related to COVID-19 or any pneumonia [14, 15]. It is imperative to be aware of the potential use of anticoagulants and anti-cytokine therapies as conceivable therapeutic options, which need to be further explored in clinical trials. In such cases, when there is evidence of cardiac injury as indicated by elevated troponins, possibilities such as myocardial microthrombi should be considered. In patients with established or suspected COVID-19 normal hs-cTnT/I and BNP/NT-proBNP concentrations, of course always in conjunction with vital parameters including pulse oximetry, can reassure physicians that outpatient management is feasible [16]. These insights can help overcome the limitations in determining the prognosis and stratification of patients as well as predicting their mortality. The cardiovascular system has been shown to be a major contributor to the proportion of deaths classified as “non-cardiovascular” by current classification schemes. An example of this is severe sepsis, mortality rates of which have a high contribution from dysfunction of the cardiac system, determined by the enzymes discussed above. Various other cardiac and vascular biomarkers are being studied in ongoing COVID-19 research. An example of this is the emerging data that growth differentiation factor 15 (GDF-15), a member of the transforming growth factor β superfamily that is released by stress due to change in hemodynamics as well as inflammation has better prognostic accuracy than established biomarkers in patients with COVID-19.
Cardiac troponin provides incremental prognostic information, only in addition to other routinely available variables. These include vital signs, clinical judgment, and other inflammatory markers such as C-reactive protein and D-dimer. Moreover, the increased implementation of these markers, such as elevated cardiac troponin in routine practice might result in inappropriate diagnostic and therapeutic interventions [17]. For example, some clinicians may elect to perform a coronary angiography in the setting of an isolated cardiac troponin elevation. These elevations would likely be in the setting of supply-demand imbalance, and less likely due to type 1 acute myocardial injury. These increased interventions also serve as a possible cause for increased harm to patients as well as the medical care team due to increased exposure to COVID-19 patients. Even non-invasive investigations may be associated with the harm caused due to the risk associated with unnecessarily transporting critically ill patients through the hospital. Hence, firm indications for testing are advocated for [18]. However, when appropriate indications are present, one should not withhold essential evaluations. There is concern that measuring cardiac troponin during the initial blood sampling in the ED may delay patient disposition, as elevated levels require additional investigation, and possibly consultation. In patients with COVID-19 and patients with ARDS, there is currently no evidence that any intervention triggered by an elevation in cardiac troponin concentration will have an impact on patient outcomes.
As we continue to learn about COVID-19 and its cardiac consequences, widespread use of cardiac markers in routine clinical practice will increase large datasets leading to better clinical characterization, cardiac imaging, and follow up leading to a better understanding of the pathophysiological mechanisms leading to cardiomyocyte injury in COVID-19. As blood tests are routinely done on patients hospitalized with COVID-19, cardiac biomarkers are easy, cost-effective and accessible method of screening for cardiac complications of COVID-19 and determining the overall prognosis of COVID-19 patients.
In patients with COVID-19 presenting with chest discomfort or dyspnea, cardiac troponin, myoglobin, natriuretic peptides, help physicians in the initial assessment.
Small increases in cardiac troponin concentrations are frequently seen and have multiple causes including myocardial oxygen supply-demand mismatch, myocarditis, and a systemic inflammatory response syndrome.
Compared with other biomarkers, elevated peak troponin I had the greatest predictive value for mortality associated with COVID-19.
If there is clear evidence of myocardial ischemia considering all available evidence, patients should be managed as acute coronary syndromes.
Cardiac troponin, creatinine kinase, and natriuretic peptide are indicated as valuable tests in patients with worsening COVID-19.
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Written By
Meher Singha, Abhishek Madathanapalli and Raj Parikh
Submitted: October 15th, 2021Reviewed: October 26th, 2021Published: March 9th, 2022
Open access peer-reviewed chapter
